Carbohydrates play a number of important roles in the functioning of living organisms. In addition to their metabolic roles, carbohydrates are structural components of the human body covalently attached to numerous other entities such as proteins and lipids (called glycoconjugates). For example, human connective tissues and cell membranes comprise proteins, carbohydrates and a proteoglycan matrix. The carbohydrate portion of this proteoglycan matrix provides important properties to the body's structure.
A genetic deficiency of the carbohydrate-cleaving, lysosomal enzyme α-L-iduronidase causes a lysosomal storage disorder known as mucopolysaccharidosis I (MPS I) (Neufeld, E. F., and Muenzer, J. (1989). The mucopolysaccharidoses in “The Metabolic Basis of Inherited Disease” (Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., Eds.), pp. 1565–1587, McGraw-Hill, New York). In a severe form, MPS I is commonly known as Hurler syndrome and is associated with multiple problems such as mental retardation, clouding of the cornea, coarsened facial features, cardiac disease, respiratory disease, liver and spleen enlargement, hernias, and joint stiffness. Patients suffering, from Hurler syndrome usually die before age 10. In an intermediate form known as Hurler-Scheie syndrome, mental function is generally not severely affected, but physical problems may lead to death by the teens or twenties. Scheie syndrome is the mildest form of MPS I. It is compatible with a normal life span, but joint stiffness, corneal clouding and heart valve disease cause significant problems.
The frequency of MPS I is estimated to be 1:100,000 according to a British Columbia survey of all newborns (Lowry et al., Human Genetics 85:389–390 (1990)) and 1:70,000 according to an Irish study (Nelson, Human Genetics 101:355–358 (1990)). There appears to be no ethnic predilection for this disease. It is likely that worldwide the disease is underdiagnosed either because the patient dies of a complication before the diagnosis is made or because the milder forms of the syndrome may be mistaken for arthritis or missed entirely. Effective newborn screening for MPS I would likely find some previously undetected patients.
Except for bone marrow transplantation, there are no significant therapies available for MPS I. Bone marrow transplants can be effective in treating some of the symptoms of the disorder but have high morbidity and mortality in MPS I and often are not available to patients because of a lack of suitable donors. An alternative therapy available to all affected patients would provide an important breakthrough in treating and managing this disease.
Enzyme replacement therapy has long been considered a potential therapy for MPS I following the discovery that α-L-iduronidase can correct the enzymatic defect in Hurler cells in culture. In this corrective process, the enzyme containing a mannose-6-phosphate residue is taken up into cells through receptor-mediated endocytosis and transported to the lysosomes where it clears the stored substrates, heparan sulfate and dermatan sulfate. Application of this therapy to humans has previously not been possible due to inadequate sources of α-L-iduronidase in tissues. The enzyme replacement concept was first effectively applied to Gaucher patients in a modified placental glucocerebrosidase. The delivery and effective uptake of glucocerebrosidase in Gaucher patients demonstrated that an enzyme could be taken up in vivo in sufficient quantities to provide effective therapy.
For α-L-iduronidase enzyme therapy in MPS I, a recombinant source of enzyme has been needed in order to obtain therapeutically sufficient supplies of the enzyme. The mammalian enzyme was cloned in 1990 (Stoltzfus et al., J. Biol. Chem. 267:6570–6575 (1992), and the human enzyme was cloned in 1991 (Moskowitz et al., FASEB J 6:A77 (1992)).